MARINA DEL REY, CALIF. — Cyclophosphamide is most likely to help scleroderma interstitial lung disease patients early in the course of their disease if they have extensive lung fibrosis, high Rodnan skin scores, and documented declines in forced vital capacity, according to findings from an unpublished subgroup analysis presented by Dr. Philip Clements, professor of medicine at the University of California, Los Angeles.
The news comes from ongoing analysis of the Scleroderma Lung Study, and is soon to be published, according to Dr. Clements. He was a lead investigator in the randomized, controlled clinical trial, which compared a 12-month course of cyclophosphamide given to 79 patients with systemic sclerosis interstitial lung disease (SSc-ILD) against placebo given to 79.
At 18 months, treated patients improved slightly over baseline forced vital capacity (FVC), whereas patients in the placebo group declined. The treatment difference between the two groups was 4.16% in favor of the cyclophosphamide patients (Am. J. Respir. Crit. Care. Med. 2007;176:1026-34).
The treatment differences “collapsed at 24 months, unfortunately,” Dr. Clements said.
However, in subsequent analysis, he and his colleagues identified a subset of patients who responded better to treatment: those with Rodnan skin thickness scores greater than 24 and fibrosis involving more than 50% of a lower-lung field.
Radiologists assessed the extent of lung fibrosis by visually inspecting high-resolution thoracic CT images. A software program has been developed to do the scoring, and should be available to clinicians within 3 years, Dr. Clements said.
For the subset of patients, FVC at 18 months in the treated group was 73% of predicted values for healthy, age-matched controls, but it was 63% of predicted values in the placebo group, although the treatment differences again collapsed at 24 months.
Even so, “the more fibrosis at baseline, the more likely [patients] are to respond,” Dr. Clements said. “Thick skin suggests their lungs are likely to respond to cyclophosphamide.” Additional analysis is planned to assess the clinical relevance of the findings, he said.
Patients from the Scleroderma Lung Study, which ran in 2000-2004, have been followed for an average of 8 years. So far, “cancer and death have not been associated with cyclophosphamide therapy,” Dr. Clements said.
Given the results, he said he treats SSc-ILD patients with cyclophosphamide if they have mild to moderate restrictive lung disease and are within 7 years of scleroderma diagnosis.
They must also have FVCs that are lower than 80% of predicted values, along with fibrosis involving 25% or more of any lung field accompanied by ground-glass opacifications and dyspnea involving difficulty in climbing two or three flights of stairs.
With those patients, “my treatment approach is similar to that of the National Institutes of Health's lupus nephritis protocol,” Dr. Clements said. The protocol includes the following:
▸ Pulse cyclophosphamide IV (500-750 mg/m
▸ Repeat pulmonary function tests every 3 months while patient is on cyclophosphamide.
▸ Upon completion of the infusion, switch to long-term mycophenolate mofetil (2-3 g/day orally).
Azathioprine (3-5 mg/kg per day) is an option if mycophenolate mofetil cannot be tolerated.
Mycophenolate mofetil is the subject of Scleroderma Lung Study II, which will compare a 2-year course of the drug in SSc-ILD patients against a 1-year course of cyclophosphamide, followed by placebo.
Mycophenolate mofetil “looks promising,” Dr. Clements said, based on several small, observational studies.
About 30 patients have enrolled in the trial since last November. “We need 150,” he said.
Information on the trial can be accessed on the Web at http://sls.med.ucla.educlinicaltrials.gov
Disclosures: Dr. Clements disclosed that he is a member of Gilead Sciences Inc.'s pulmonary hypertension advisory board.